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Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity.

ABSTRACT: AIMS/HYPOTHESIS:During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-?H1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. METHODS:EndoC-?H1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. RESULTS:EndoC-?H1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-?H1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION:The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. DATA AVAILABILITY:Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

SUBMITTER: Oshima M

PROVIDER: S-EPMC6946759 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity.

Oshima Masaya M Pechberty Séverine S Bellini Lara L Göpel Sven O SO Campana Mélanie M Rouch Claude C Dairou Julien J Cosentino Cristina C Fantuzzi Federica F Toivonen Sanna S Marchetti Piero P Magnan Christophe C Cnop Miriam M Le Stunff Hervé H Scharfmann Raphaël R

Diabetologia 20191203 2

<h4>Aims/hypothesis</h4>During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell ...[more]

PMID: 31796987

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Project description:In bone diseases such as osteonecrosis and osteoporosis, a shift toward a preferential differentiation of mesenchymal stromal cells (MSC) into adipocytes at the expense of the osteoblastic lineage is described, leading to excessive accumulation of adipocytes in the bone marrow of the patients. The influence of cytokines and adipokines secreted by adipocytes on skeletal health is already well-documented but the impact of free fatty acids release on bone cell biology and viability is an emerging concept. We have previously demonstrated that the saturated fatty acid (SFA) palmitate (Palm) is cytotoxic for human MSC (hMSC) and osteoblasts whereas oleate (Ole), a monounsaturated fatty acid (MUFA), has no toxic effect. Moreover, Ole protects cells against lipotoxicity. Our observations led us to propose that the toxicity of the SFA is not correlated to its intracellular accumulation but could rather be related to the intracellular SFA/MUFA ratio, which finally determines the toxic effect of SFA. Therefore, in the present study, we have investigated the potential protective role of the enzyme stearoyl-CoA 9-desaturase 1 (SCD1) against the deleterious effects of Palm. SCD1 is an enzyme responsible for desaturation of SFA to MUFA; its activation could therefore lead to modifications of the intracellular SFA/MUFA ratio. In the present study, we showed that hMSC express SCD1 and liver X receptors (LXRs), transcription factors regulating SCD1 expression. Human MSC treatment with a LXRs agonist triggered SCD1 expression and drastically reduced Palm-induced cell mortality, caspases 3/7 activation, endoplasmic reticulum stress and inflammation. We also observed that, in the presence of Palm, the LXRs agonist provoked lipid droplets formation, augmented the total cellular neutral lipid content but decreased the SFA/MUFA ratio when compared to Palm treatment alone. Addition of an inhibitor of SCD1 activity abrogated the positive effects of the LXRs agonist, suggesting that SCD1 could play a key role in protecting hMSC against lipotoxicity.

Dataset Information

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity.

Publications

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity.

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